Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMBINATION OF ~-AMINOBUTYRIC ACID MODULATORS AND 5-HT~e RECEPTOR
ANTAGONISTS
BACKGROUND OF THE INVENTION
The present invention relates . to pharmaceutical compositions containing y
aminobutyric acid modulators or pharmaceutically acceptable salts thereof and
5-HT~B
receptor antagonists or pharmaceutically acceptable salts thereof, and to
their medicinal use
for treating disorders associated with the central nervous system.
U.S. Patent Nos. 6,462,048, 6,258,953, 6,380,186, and 6,323,229, and U.S.
Patent
Publication Nos. 2002/0091119 and 2003/0083337 describe certain aralkyl and
aralkylidene
heterocyclic lactams and imides that are 5-HT,B receptor antagonists and that
are used in the
compositions of the present invention. Other 5-HT, receptor antagonists are
described in
European Patent Publications 701,819, 434,561 and 343,050, PCT publications WO
94/21619, WO 95/31988, and WO 96/00720, Glennon et al., "5-HT,~ Serotonin
Receptors",
Clinical Drug Res. Dev., 22, 25-36 (1991 ), and G Maura et al., J. Neurochem,
66 (1 ), 203-209
(1996). These references describe 5-HT~ receptor antagonists, including 5-HT~e
receptor
antagonists, as useful in the treatment of, for example, migraine, depression,
obsessive
compulsive disorder, post-traumatic stress disorder (PTSD), and eating
disorders, as well as
other disorders associated with the central nervous system.
y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the
patient in
the central nervous system (CNS). GABA receptors can be found in 60-80% of CNS
neurons.
Allosteric facilitation of GABA receptors occurs at several distinct sites;
the compounds which
bind to these receptor sites have been used as sedatives and anxiolytics.
GABA modulators have also been disclosed to be useful in antiseizure therapy
for
central nervous system disorders such as epilepsy, Huntington's chorea,
cerebral ischemia,
Parkinson's disease, tardive dyskinesia and spasticity. GABA modulators have
also been
disclosed to be useful antidepressants, anxiolytics and antipsychotics.
Commonly assigned U.S. Pat. No. 4,024,175, which is hereby incorporated by
reference, discloses that GABA modulators have utility in the treatment of
treatment-resistant
anxiety, psychotic disorders and conditions, and mood disorders and
conditions.
GAGA modulators or agonists well known in the art include muscimol, progabide,
riluzole, baclofen, gabapentin (Neurontin ~), vigabatrin, valproic acid,
(Depakene~,
Depakote~) tiagabine (Gabitril~), lamotrigine (Lamictal~), pregabalin,
topiramate
(Topamax~) and analogs, derivatives, prodrugs and pharmaceutically acceptable
salts
thereof.
WO 01/24791 discloses the synergistic combinations of NK1 antagonists and GABA
analogs and modulators.
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The term "GABA", where used in the description and the appendant claims, is
synonymous with the term "gamma-aminobutyric acid." These terms are used
interchangeably throughout the description and claims.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition for treating,
for
example, a disorder or condition selected from the group consisting of
hypertension,
depression, generalized anxiety disorder, phobias, posttraumatic stress
disorder, avoidant
personality disorder, sexual dysfunction, eating disorders, obesity, chemical
dependencies,
cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive
disorder, panic
disorder, memory disorders, Parkinson's diseases, endocrine disorders,
cerebellar ataxia,
gastrointestinal tract disorders, negative symptoms of schizophrenia,
premenstrual syndrome,
Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,
trichotillomania,
kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and
headache in a
mammal, preferably a human, comprising:
(i) a y-aminobutyric acid modulator or a pharmaceutically acceptable salt
thereof,
(ii) a 5-HT~B receptor antagonist or a pharmaceutically acceptable salt
thereof,
wherein the 5-HT~e receptor antagonist is selected from the group consisting
of
(A) a compound of the formula I -
Rl R2 0
N/Rs
~ R5 R4
wherein, in formula I:
R' is a group of the formula G', G2, G3, G4, G5, G6 or G' depicted below,
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G'
'N
~Ri 3~a
N
Rs G2
'N
~R13~ I/a
_ . Rs
P G3
N~
Rs
R~
N~
G4
N~
Rs
E
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Rs Gs
N~
R9
R~
N /
G6
NR6R9
P
N
,n, ~ nr
G'
P
NR6R9
N
.n. ~ nr
a is zero to eight;
each R'3 is, independently, (C~ -C4)alkyl or a (C, -C4)methylene bridge from
one of
the ring carbons of the piperazine or piperidine ring of G' or G2,
respectively, to the same or
another ring carbon or a ring nitrogen of the piperazine or piperidine ring of
G' or G2,
respectively, having an available bonding site, or to a ring carbon of R6
having an available
bonding site;
E is oxygen, sulfur, SO or SOz;
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X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C, -Cs)alkyl, hydroxy,
trifluoromethyl, (C~ -Cs)alkoxy, --SOt (C, -C6)alkyl wherein t is zero, one or
two, --COZR'° or
-CONR"R'2,
RZ is hydrogen, (C~ -C4)alkyl, phenyl or naphthyl, wherein said phenyl or
naphthyl is
optionally substituted with one or more substituents independently selected
from the group
consisting of chloro, fluoro, bromo, iodo, (C, -C6)alkyl, (C~ -C6)alkoxy,
trifluoromethyl, cyano
and -SOk(C, -Cs)alkyl wherein k is zero, one or two;
R3 is --(CHZ)mB, wherein m is zero, one, two or three and B is hydrogen,
phenyl,
naphthyl or a 5 or 6 membered heteroaryl group containing from one to four
hetero-atoms in
the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl
groups is
optionally substituted with one or more substituents independently selected
from the group
consisting of chloro, fluoro, bromo, iodo, (C, -Cs)alkyl, (C~ -Cs)alkoxy, (C~ -
Cs) alkoxy-(C~ -
Cs)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, --COOH and -
SO"(C~ -Cs)alkyl
wherein n is zero, one or two;
R4 is (C,-C6)alkyl or C6-C,° aryl;
or R3 and R4 may optionally be taken together with the nitrogen to which they
are
attached to form a five to seven membered heteroalkyl ring, wherein any two of
the carbon
atoms of said heteroalkyl ring is optionally replaced with a heteroatom
selected from the group
consisting of nitrogen, oxygen or sulfur e(~C,_. ., pyrrolidine,
isoxazolidine, 1,3-oxazolidin-3-yl,
isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-
yl, piperidine,
thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,
tetrahydrothiadiazine,
morpholine, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, piperazine,
etc.); wherein said
heteroalkyl ring may optionally be substituted by aryl or heteroaryl e~.c~.,
furyl, thienyl, thiazolyl,
pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl,
tetrazolyl, imidazolyl, 1,3,5-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-
thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl,
1,2,3-triazinyl, 1,3,5-triazinyl,
benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, thianaphthenyl,
isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,
indazolyl, isoquinolyl,
quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc.);
RS is hydrogen, (C~-Cs)alkyl or aryl, wherein aryl is selected from the group
consisting
of phenyl or naphthyl, wherein any of said aryl is optionally independently
substituted on any
available bonding site by any of the radicals of X;
or RS and R4 taken together form a divalent group - Y"2-;
Y is selected from the group consisting of (a) CR°R5, wherein R4 and
R5 are
independently selected from hydrogen, (C,-C6)alkyl and trifluoromethyl; (b) a
phenylene,
naphthylene or a 5 or 6 membered heteroarylene ring comprising from one to
four hetero
atoms in the heteroarylene ring, and wherein each of the foregoing phenylene,
naphthylene
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and heteroarylene rings may optionally be substituted with one or more
substituents
independently selected from the group consisting of chloro, fluoro, bromo,
iodo, (C, -C6)alkyl,
(C~ -C6)alkoxy, (C, -C6) alkoxy-(C, -Cs)alkyl-, trifluoromethyl,
trifluoromethoxy, cyano,
hydroxy, -COOH and -SO"(C~ -CB)alkyl wherein n is zero, one or two, wherein
two adjacent
ring atoms of ring Y are also ring atoms of ring A; and (c) an optionally
substituted (C~ -C4)
heteroalkyl bridge that, together with the atoms to which it is attached,
forms a five to seven
membered heterocycle containing two to four heteroatoms selected from the
group consisting
of 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-
oxazolidin-3-on-4-yl,
1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-pyrazolidin-4-on-
5-yl, 1,3-
imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl, 1,2-thiazolidin-1,1,3-
trion-4-yl, 1,2-
thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin-
4-on-5-yl,
tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl, morpholin-3,5-dion-2-
yl, 2,3-dihydro-
1,4-oxazin-3-on-2-yl, tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-
2,4-dion-5-yl,
tetrahydro-1,2-thiazin-3-on-4-yl, thiomorpholin-3-on-2-yl, thiomorpholin-3,5-
dion-2-yl, 2,3-
dihydro-1,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-
pyridazin-3-on-
4-yl, hexahydro-1,3-diazin-4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl,
piperazin-2-on-3-yl,
piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-6-yl, 5,6-dihydro-
1,3,4-thiadiazin-5-
on-6-yl, 1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl,
tetrahydro-1,2,4-
oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-
6-yl, 5,6-dihydro-
1-2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl, 1,2,4-trazin-6-on-5-
yl, hexahydro-1,2-
oxazepin-3-on-2-yl, hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-oxazepin-3-
on-2-yl,
hexahydro-1,4-oxazepin-3,5-dion-2-yl, hexahydro-1,4-oxazepin-3,5-dion-6-yl,
2,3,5,6-
tetrahydro-1-4-oxazepin-5,7-dion-6-yl, hexahydro-1,4-oxazepin-5-on-6-yl,
hexahydro-1,3-
oxazepin-2,4-dion-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-
thiazepin-3-on-2-yl,
2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl, hexahydro-1,4-thiazepin-3,5-dion-2-
yl, hexahydro-
1,4-thiazepin-3,5-dion-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl, 6,7-
dihydro-1,4-
thiazepin-5-on-6-yl, hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-
diazepin-3-on-4-yl,
hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl,
hexahydro-1,4-
diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl, hexahydro-1,3,5-
thiadiazepin-3-on-
7-yl, 4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl, and 2,3,5,6-tetrahydro-
1,2,4-triazepin
3,5-dion-7-yl; wherein the substituents on any of the carbon atoms capable of
supporting an
additional bond, of said (C~ -C4) heteroalkyl bridge, are chloro, fluoro, (C~ -
Cg)alkyl, (C,
C6)alkoxy, trifluoromethyl or cyano; wherein the substituents on any of the
nitrogen atoms
capable of supporting an additional bond, of said (C, -C4) heteroalkyl bridge,
are (C~
C6)alkyl or trifluoromethyl,
n2 is one, two, three or four, with the proviso that n2 is one when Y is not
CR4R5;
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R6 is selected from the group consisting of hydrogen, (C~ -CB)alkyl optionally
substituted with (C, -Cs)alkoxy or one to three fluorine atoms, or [(C, -
C4)alkyl]aryl wherein
the aryl moiety is phenyl, naphthyl, or heteroaryl-(CHz)q -, wherein the
heteroaryl moiety is
selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,
benzothiazolyl,
benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four,
and wherein said
aryl and heteroaryl moieties may optionally be substituted with one or more
substituents
independently selected from the group consisting of chloro, fluoro, bromo,
iodo, (C~-C6)alkyl,
(C,-CB)alkoxy, trifluoromethyl, cyano and -SO9(C~-C6)alkyl, wherein g is zero,
one or two;
R' is selected from the group consisting of hydrogen, (C,-C6)alkyl, [(C~-
C4)alkyl]aryl
wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CHZ)~ -, wherein
the heteroaryl
moiety is selected from the group consisting of pyridyl, pyrimidyl,
benzoxazolyl,
benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one, two,
three or four, and
wherein said aryl and heteroaryl moieties may optionally be substituted with
one or more
substituents independently selected from the group consisting of chloro,
fluoro, bromo, iodo,
(C~-Cs)alkyl, (C~-Cs)alkoxy, trifluoromethyl, --C(=O)--(C~-C6)alkyl, cyano and
-SO~(C~-Cs)alkyl,
wherein j is zero, one or two;
or Rs and R' taken together form a C2-C4 alkylene chain;
R8 is hydrogen or (C~-C3)alkyl;
R9 is hydrogen or (C~-C6)alkyl;
or Rs and R9, together with the nitrogen atom to which they are attached, form
a 5 to
7 membered heteroalkyl ring that contains, in addition to the nitrogen atom to
which R6 and R9
are attached, from zero to four heteroatoms selected from the group consisting
of nitrogen,
sulfur and oxygen;
and p is one, two, or three;
each of R'°, R" and R'2 is selected, independently, from the groups set
forth in the
definition of RZ ; or R" and R'2, together with the nitrogen to which they are
attached, form a
5 to 7 membered heteroalkyl ring that may contain, in addition to the nitrogen
atom to which
R" and R'2 are attached, from zero to four heteroatoms selected from the group
consisting of
nitrogen, sulfur and oxygen, and
the broken lines indicate optional double bonds, with the proviso that when
the
broken line in GZ is a double bond, R$ is absent;
(B)
a compound of the formula II
R~ R5 R3
N RZ
~X~m I
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_g_
wherein in Formula II,
R' is a group of the formula G', G2, G3, G4, G8 or G6' wherein G', G2, G3, G4,
and Gs
are each defined as for formula I, and G8 is depicted below
Rs
N~
Rs
D
Gg
m is 0, 1, 2, 3 or 4;
D is oxygen, sulfur, SO, S02, or NR';
a is zero to eight;
pis1,2or3;
E is oxygen, sulfur, SO or SO2;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C,-CB)alkyl, hydroxy,
trifluoromethyl, (C~-Cs)alkoxy, -S(O~(C,-C6)alkyl wherein t is 0, 1 or 2, -
COZR'° or -
CONR" R'Z;
RZ is -(CH2)yB, wherein y is 0, 1, 2 or 3, and B is hydrogen, phenyl, naphthyl
or a 5 or
6 membered heteroaryl group containing from one to four heteroatoms in the
ring, and
wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may
optionally be
substituted with one or more substituents independently selected from chloro,
fluoro, bromo,
iodo, (C,-Cs)alkyl, (C~-CB)alkoxy, (C~-C6)alkoxy-(C~-Cs)alkyl-,
trifluoromethyl, trifluoromethoxy,
cyano, hydroxy, -COOH and -SO~(C,-Cs)alkyl wherein n is 0, 1 or 2;
R3 and R4 are each independently hydrogen, (C~-C4)alkyl or -(CHZ)q-J wherein q
is 0,
1, 2 or 3, and J is phenyl or naphthyl, wherein said phenyl or naphthyl may be
optionally
substituted with one to three substituents independently selected from the
group consisting of
chloro, fluoro, bromo, iodo, (C,-C6)alkyl, (C,-C6)alkoxy, trifluoromethyl,
cyano and -S(O)k(C,
C6)alkyl wherein k is 0, 1 or 2;
R5 is hydrogen or (C~-C3)alkyl;
Rs is selected from the group consisting of hydrogen, (C~-Cs)alkyl optionally
substituted
with (C,-C6)alkoxy or one to three fluorine atoms, or [(C~-C4)alkyl]aryl
wherein the aryl moiety is
phenyl, naphthyl, or heteroaryl-(CH2)qZ-, wherein the heteroaryl moiety is
selected from the
group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl,
benzisoxazolyl and
benzisothiazolyl and q2 is zero, one, two, three or four, and wherein said
aryl and heteroaryl
moieties may optionally be substituted with one or more substituents
independently selected
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_g_
from the group consisting of chloro, fluoro, bromo, iodo, (C~-C6)alkyl, (C~-
C6)alkoxy,
trifluoromethyl, cyano and -SO9(C~-Cg)alkyl, wherein g is zero, one or two;
R' is selected from the group consisting of hydrogen, (C~-Cs)alkyl, [(C~-
C4)alkyl]aryl
wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CHZ)~ , wherein
the heteroaryl moiety
is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,
benzothiazolyl,
benzisoxazolyl and benzisothiazolyl and r is zero, one, two, three or four,
and wherein said aryl
and heteroaryl moieties may optionally be substituted with one or more
substituents
independently selected from the group consisting of chloro, fluoro, bromo,
iodo, (C~-C6)alkyl,
(C~-C6)alkoxy, trifluoromethyl, -C(=O)-(C,-Cs)alkyl, cyano and -SO~(C~-
Cg)alkyl, wherein j is
zero, one or two;
or Re and R'taken together form a 2 to 4 carbon chain;
R$ is hydrogen or (C,-C3)alkyl;
R9 is hydrogen or (C,-Cs)alkyl;
or R6 and R9, together with the nitrogen atom to which they are attached, form
a 5 to
7 membered heteroalkyl ring that contains, in addition to the nitrogen atom to
which R6 and R9
are attached, from zero to four heteroatoms selected from the group consisting
of nitrogen,
sulfur and oxygen;
each of R'°, R" and R'2 is selected, independently, from the groups set
forth in the
definition of R3 ; or R" and R'2, together with the nitrogen to which they are
attached, form a
5 to 7 membered heteroalkyl ring that may contain, in addition to the nitrogen
atom to which
R" and R'2 are attached, from zero to four heteroatoms selected from the group
consisting of
nitrogen, sulfur and oxygen, and
each R'3 is, independently, (C~-C4)alkyl or a (C,-C4)methylene bridge from one
of the
ring carbons of the piperazine or piperidine ring of G' or G2, respectively,
to the same or
another ring carbon or a ring nitrogen of the piperazine or piperidine ring of
G' or GZ,
respectively, having an available bonding site, or to a ring carbon of Rs
having an available
bonding site;
with the proviso that when B is hydrogen, t is not zero; and
with the proviso that when the broken line in formula GZ is a double bond, R8
is
absent;
and optionally
(iii) a pharmaceutically acceptable carrier.
The present invention also relates to:
a pharmaceutical composition for treating, for example, a disorder or
condition that
can be treated by enhancing serotonergic neurotransmission in a mammal,
preferably a
human, comprising components (i), (ii) and optionally (iii) defined in the
previous paragraphs;
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a method for treating a disorder or condition as defined in the previous
paragraphs in
a mammal, preferably a human, comprising administering to a mammal in need of
such
treatment components (i) and (ii) as defined in the previous paragraphs;
a method for treating a disorder or condition that can be treated by enhancing
serotonergic neurotransmission in a mammal, preferably a human, comprising
administering
to a mammal in need of such treatment components (i) and (ii) as defined in
the previous
paragraphs.
The 5-HT,B receptor antagonist of the formula I or II defined herein of the
compositions and the methods of the invention may be used in an amount that is
a serotonin
receptor antagonizing or agonizing effective amount.
In the pharmaceutical compositions and methods of the invention, components
(i) and
(ii) as defined in the previous paragraphs may also be combined with a 5-HT,A
antagonist or a
pharmaceutically acceptable salt thereof, wherein the amounts of each of
components (i), (ii)
and the 5-HT,A antagonist or a pharmaceutically acceptable salt thereof are
such that the
combination of components (i), (ii) and the 5-HT,A antagonist or a
pharmaceutically
acceptable salt thereof is effective in treating a disorder or condition as
defined in the
previous paragraphs. For example, the method of the invention may further
comprise
administering a 5-HT,A antagonist or a pharmaceutically acceptable salt
thereof, wherein the
amounts of each of components (i), (ii) and the 5-HT~A antagonist or a
pharmaceutically
acceptable salt thereof are such that the combination of components (i), (ii)
and the 5-HT,A
antagonist or a pharmaceutically acceptable salt thereof is effective in
treating the disorder or
condition.
DETAILED DESCRIPTION OF THE INVENTION
"Enhancing serotonergic neurotransmission," as used herein, refers to
increasing or
improving the neuronal process whereby serotonin is released by a pre-synaptic
cell upon
excitation and crosses the synapse to stimulate or inhibit the post-synaptic
cell.
"Chemical dependency," as used herein, means an abnormal craving or desire
for, or
an addiction to a drug. Such drugs are generally administered to the affected
individual by
any of a variety of means of administration, including oral, parenteral, nasal
or by inhalation.
Examples of chemical dependencies treatable by the methods of the present
invention are
dependencies on alcohol, nicotine, cocaine, amphetamine and other
psychostimulants,
morphine, heroin and other opioid agonists, Phenobarbital and other
barbiturates, and
benzodiazepines such as diazepam and others. "Treating a chemical dependency,"
as used
herein, means reducing or alleviating such dependency.
A "unit dosage form" as used herein is any form that contains a unit dose of
the y-
aminobutyric acid modulator or a pharmaceutically acceptable salt thereof, of
the compound
of formula I or formula II or a pharmaceutically acceptable salt thereof, or
of the r-
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aminobutyric acid modulator or pharmaceutically acceptable salt thereof and
the compound of
formula I or formula II or pharmaceutically acceptable salt thereof. A unit
dosage form may
be, for example, a tablet or a capsule. A unit dose may be an amount which may
be
predetermined, for example, by a physician.
The term "GAGA modulator" as used herein refers to a compound that either is
structurally related to the neurotransmitter GABA but does not interact with
the GABA
receptor (e.g. gabapentin), or interacts with the GABA receptors, or is
converted metabolically
into GABA or a GAGA modulator; or is an inhibitor of GABA uptake or
degradation; or is a
GABA receptor subtype-selective antagonist and/or agonist. This definition
includes
pharmaceutically acceptable salts, prodrugs or pharmaceutically acceptable
salts of said
prodrugs.
Examples of the disorders or conditions which may be treated by the methods,
compositions and kits of this invention are as follows:
depression, including depression in cancer patients, depression in Parkinson's
patients, Postmyocardial Infarction depression, Subsyndromal Symptomatic
depression,
depression in infertile women, pediatric depression, major depression, single
episode
depression, recurrent depression, child abuse induced depression, post partum
depression,
DSM-IV major depression, treatment-refractory major depression, bipolar
depression BP I,
bipolar depression BP II, depression in patients with human immunodeficiency
virus (HIV),
severe depression, psychotic depression, post-stroke depression, neuropathic
pain, manic
depressive illness, including manic depressive illness with mixed episodes and
manic
depressive illness with depressive episodes, seasonal affective disorder, and
major
depression with dysthymia.
phobias, including agoraphobia, social phobia and simple phobias;
sexual dysfunction, including premature ejaculation;
eating disorders, including anorexia nervosa and bulimia nervosa;
chemical dependencies, including addictions to alcohol, cocaine, heroin,
phenolbarbitol, nicotine and benzodiazepines;
memory disorders, including dementia, amnestic disorders, and age-related
cognitive
decline (ARCD);
Parkinson's diseases, including dementia in Parkinson's disease, neuroleptic-
induced
parkinsonism and tardive dyskinesias;
endocrine disorders, including hyperprolactinaemia;
vasospasm, including a vasospasm in the cerebral vasculature;
gastrointestinal tract disorders, including gastrointestinal tract disorders
involving
changes in motility and secretion;
cancer, including small cell lung carcinoma;
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headache, including headache associated with vascular disorders.
Preferred disorders or conditions that may be treated by the methods,
compositions
and kits of this invention are migraine, depression, obsessive compulsive
disorder, post-
traumatic stress disorder (PTSD), and eating disorders.
As used herein, "mammal" means any member of the class Mammalia. As an
example, the mammal in need of the treatment may be a human. As another
example, the
mammal in need of the treatment may be a mammal other than a human.
The methods of this invention also encompass treating the diseases or
conditions
described herein by the co-administration of two separate pharmaceutical
compositions. In
this latter embodiment, a first composition comprises a y-aminobutyric acid
modulator, and a
second composition comprises a 5-HT~B receptor antagonist of the formula I or
II. These first
and second compositions are preferably co-administered either simultaneously,
or in a
specifically timed manner.
A prodrug of the r-aminobutyric acid modulator, of the 5-HT,B receptor
antagonist of
the formula I or II, or of both the y-aminobutyric acid modulator and the 5-
HT,B receptor
antagonist also may be used in the composition and method of the invention.
The term
"prodrug" refers to compounds that are drug precursors which, following
administration,
release the drug in vivo via some chemical or physiological process (e.g., a
prodrug on being
brought to the physiological pH is converted to the desired drug form). A
prodrug of any or all
of the y-aminobutyric acid modulators or the 5-HT~B receptor antagonists may
be used in the
methods, kits, and compositions of the instant invention. In general, prodrugs
are functional
derivatives of these compounds which are readily convertible in vivo.
Conventional
procedures for the selection and preparation of suitable prodrug derivatives
are described, for
example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985 and can be
achieved using
methods well known to those skilled in the art. All such prodrugs are within
the scope of the
combinations, pharmaceutical compositions, methods and kits of this invention.
Upon cleavage, exemplary prodrugs release the corresponding free acid (where
applicable), and such hydrolyzable ester-forming residues of the prodrugs of
this invention
include but are not limited to carboxylic acid substituents wherein the free
hydrogen is
replaced by (C~-C4)alkyl, (CZ-C~Z)alkanoyloxymethyl, (C4-C9)1-
(alkanoyloxy)ethyl, 1-methyl-1-
(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl
having from 3
to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-
(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-
(alkoxycarbonyl)aminomethyl
having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from
4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-
(C,-
CZ)alkylamino(CZ-C3)alkyl (such as N,N-dimethylaminoethyl), carbamoyl-(C~-
Cz)alkyl, N,N-
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di(C,-CZ)-alkylcarbamoyl-(C,-CZ)alkyl, piperidino-, pyrrolidino-, or
morpholino(CZ-C3)alkyl, and
the like.
The present invention also relates to the pharmaceutically acceptable acid
addition
salts of compounds of the formula I or formula II. The acids which are used to
prepare the
pharmaceutically acceptable acid addition salts of the aforementioned base
compounds of this
invention are those which form non-toxic acid addition salts, i.e., salts
containing
pharmacologically acceptable anions, such as the hydrochloride, hydrobromide,
hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,
citrate, acid citrate,
tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate,
benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and
pamoate i.e.,
1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
The invention also relates to base addition salts of formula I or formula II.
The
chemical bases that may be used as reagents to prepare pharmaceutically
acceptable base
salts of those compounds of formula I or formula II that are acidic in nature
are those that form
non-toxic base salts with such compounds. Such non-toxic base salts include,
but are not
limited to those derived from such pharmacologically acceptable cations such
as alkali metal
cations (e.~c ., potassium and sodium) and alkaline earth metal cations
Le.c~., calcium and
magnesium), ammonium or water-soluble amine addition salts such as N-
methylglucamine-
(meglumine), and the lower alkanolammonium and other base salts of
pharmaceutically
acceptable organic amines.
The compounds of this invention include all stereoisomers e(~.c~., cis and
traps isomers)
and all optical isomers of compounds of the formula I or formula II (e.~C ., R
and S enantiomers),
as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds of this invention may contain C=C double bonds. When such bonds
are present, the compounds of the invention exist as cis and traps
configurations and as
mixtures thereof.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein,
as well as
the alkyl moieties of other groups referred to herein (e.d, alkoxy), may be
linear or branched,
and they may also be cyclic e(rc~., cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl) or be linear
or branched and contain cyclic moieties. Unless otherwise indicated, halogen
includes fluorine,
chlorine, bromine, and iodine.
The term "a 5 or 6 membered heteroaryl group containing from one to four
heteroatoms
in the ring", as used herein, unless otherwise indicated, includes but is not
limited to furyl,
thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,
triazolyl, tetrazolyl,
imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-
thiadiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
1,2,4-triazinyl, 1,2,3-
triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl,
benzisoxazolyl,
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benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl,
isobenzofuranyl, isoindolyl,
indolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl,
quinazolinyl or benzoxazinyl.
The term "a 5 to 7 membered heteroalkyl ring that may contain from one to four
heteroatoms selected from nitrogen, sulfur and oxygen", as used herein, unless
otherwise
indicated, includes but is not limited to pyrrolidine, isoxazolidine, 1,3-
oxazolidin-3-yl,
isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-
yl, piperidine,
thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,
tetrahydrothiadiazine,
morpholine, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, piperazine.
The following are more specific embodiments of groups G' and GZ of the
compound
of formula I:
s
G'-a
N
R~s
N
R6 G~ _b
N
N R~s
Ri3~R6 Gi_c
N
N
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Rs G' _d
"J
R6 Gi-a
I
N
N
'N
N
Gl-f
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Rs Gt_g
i~
Rs
G1-h
N
N
GZ-a
N Rs
N
wherein each R'3 is, independently, (C, -C4)alkyl or a (C, -C4)methylene
bridge from one of
the ring carbons of the piperazine or piperidine ring of G' or G2,
respectively, to the same or
another ring carbon or a ring nitrogen of the piperazine or piperidine ring of
G' or Gz,
respectively, having an available bonding site, or to a ring carbon of Rg
having an available
bonding site.
Preferred compounds of the formula I include those wherein R' is
--N N-Rs,
U
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RB is (C,-Cs)alkyl, such as methyl, and R2 is hydrogen.
Other preferred compounds of formula I include those wherein R3 is hydrogen,
phenyl
or benzyl optionally substituted by chloro, fluoro, bromo, iodo, (C,-CB)alkyl
or trifluoromethyl.
Other preferred compounds of formula I include those wherein R4 is hydrogen or
(C,-
C6)alkyl, such as methyl.
More preferred compounds of formula I include those wherein R' is
--N N-R6,
U
R6 is (C,-Cs)alkyl and Rz is hydrogen; R3 is phenyl or benzyl optionally
substituted by
chloro, fluoro, bromo, iodo, (C,-C6)alkyl or trifluoromethyl; and R4 is
hydrogen or (C,-Cs)alkyl.
Preferred compounds of the formula I also include those wherein Y, together
with the
atoms to which it is attached, forms an optionally substituted five to seven
membered
heterocycle selected from the group consisting of 1,3-thiazolidin-2,4-dion-5-
yl, 1,3-
imidazolidin-2,4-dion-5-yl, thiomorpholin-3-on-2-yl or morpholin-3-on-2-yl.
Preferred compounds of the formula I also include those wherein R3 is phenyl
or -
(CHz)-phenyl, wherein said phenyl groups are optionally substituted with one
or more
substituents independently selected from the group consisting of chloro,
fluoro, bromo, iodo,
(C,-C6)alkyl, (C,-C6)alkoxy, (C,-Cs)alkoxy-(C,-C6)alkyl-, trifluoromethyl,
trifluoromethoxy,
cyano, hydroxy, --COOH and -SO~(C~-C6)alkyl wherein n in -SO"(C~-Cs)alkyl is
zero, one or
two.
Preferred compounds of the formula I also include those wherein R5 is hydrogen
or
methyl.
Preferred compounds of the formula I also include those wherein X is hydrogen,
fluoro
or chloro, preferably wherein X is hydrogen.
Preferred compounds of the formula I also include those wherein R4 and R5,
together
with the nitrogen to which they are attached, form a 5 to 7 membered
heteroalkyl ring that is
selected from the group consisting of pyrrolidine, isoxazolidine, 1,3-
oxazolidin-3-yl,
isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-
yl, piperidine,
thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,
tetrahydrothiadiazine,
morpholine, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, and
piperazine.
Preferred compounds of the formula I also include those wherein m is 0 or 1.
Preferred compounds of the formula II include those wherein R' is
N N-R6,
U
R6 is (C, -C6)alkyl and R3 is hydrogen.
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Other preferred compounds of formula II include those wherein RZ is phenyl or
benzyl
optionally substituted by chloro, fluoro, bromo, iodo, (C,-CB)alkyl or
trifluoromethyl.
Other preferred compounds of formula II include those wherein R4 is hydrogen
or (C,
-C6)alkyl.
More preferred compounds of formula II include those wherein R' is
N N-R6,
U
R6 is (C,-C6)alkyl and R3 is hydrogen; RZ is phenyl or benzyl optionally
substituted by
chloro, fluoro, bromo, iodo, (C~-Cg)alkyl or trifluoromethyl; and R4 is
hydrogen or (C,-C6)alkyl.
Preferred examples of compounds of component (ii) include:
4-benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;
4-(3,4-dichlorobenzyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
2-[2-(4-methylpiperazin-1-yl )-benzyl idene]-4-(4-trifluoromethyl phenyl)-th
iomorpholin-
3-one;
2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;
4-(3,4-dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-one;
4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
4-(3,4-dichlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-benzyl]-thiomorpholin-3-
one;
4-methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;
4-(3,4-dichlorophenyl)-2-(2-piperazin-1-ylbenzylidene)-thiomorpholin-3-one;
4-(3,4-dichlorophenyl)-2-[2-(4-methyl-(4-piperazin-1-yl)-benzylidene]-1-
oxo-thiomorpholin-3-one;
4-(3,4-dichlorophenyl)-2-[2-(4-methyl-4-oxy-piperazin-1-yl)-benzylideneJ-
thiomorpholin-3-one;
10-[4(3,4-dichlorophenyl)-3-oxo-thiomorpholin-2-yl]-2-methyl-3,42-dihydro-
pyrazino[1,2-a]indol-2-ium;
4-Benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,1-dioxothiomorpholin-3-
one;
4-(3,4-Dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-5-trifluoromethyl-
benzylidenej-
thiomorpholin-3-one;
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4-(3,4-Dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]-benzylidene}
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(4-isopropylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
4-(3,4-Dichlorophenyl)-2-[2-(4-ethylpiperazin-1-yl)-benzylidene]-thiomorpholin-
3-one;
4-(4-Chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-
one;
4-(3-Chlorophenyl)-2-[2-(4-methylpiparazin-1-yl)-benzylidene]-thiomorpholin-3-
one;
2-[2-Chloro-6-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-4-trifluoromethyl-
benzylidene]-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzyl idene]-1-oxo-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-(5-fluoro-2-piperazin-1-yl-benzylidene)-thiomorpholin-
3-one;
4-(3,4-Dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
4-Phenyl-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-
one;
2-[5-Fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-phenyl-thiomorpholin-3-
one;
4-Benzo[1,3]dioxol-5-yl-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
3-one;
2-[2-(4-tert-Butylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-
thiomorpholin-3-
one;
3-[4-(3,4-Dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-
2-
(4-methylpiperazin-1-yl)-benzonitrile;
4-(3,4-Dichlorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
3-one;
4-(3,4-Dichlorophenyl)-2-[5-methyl-2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-one;
2-[4-Chloro-2-(4-methylpiperazin-1-yl)-benzylideneJ-4-(3,4-dichlorophenyl)-
thiomorpholin-3-one;
4-(3,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
4-(2,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
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2-(4-Bromo-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl )-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(1-methylpyrrol idin-2-ylmethoxy)-benzyl idene]-
thiomorpholin-3-one;
4-(3,5-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
one;
3-one;
4-(3,4-Difluorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
4-(3,4-Dichlorophenyl)-2-[2-(octahydropyrido[1,2-a]pyrazin-2-yl)-benzylidene]-
thiomorpholin-3-one;
3-one;
3-one;
one;
one;
2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-pyridin-3-yl-thiomorpholin-3-
one;
2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-difluorophenyl)-
thiomorpholin-
2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,5-dichlorophenyl)-
thiomorpholin-
4-(3,4-Difluorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
4-(3,5-Dichlorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
4-(3,4-Dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-1-yl)-benzylidene]-
thiomorpholin-3-one;
3-one;
3-one;
one;
3-one;
4-(3,4-Difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
4-Benzo[1,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]-4-(4-fluorophenyl)-
thiomorpholin-3-
4-Benzo[1,3]dioxol-5-yl-2-[2-(2,5-dimethylpiperazin-1-yl )-benzyl idene]-
thiomorpholin-
2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]-4-phenylthiomorpholin-3-one;
one;
4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-
thiomorpholin-3-
4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene]-
thiomorpholin-3-one;
4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene]-
thiomorpholin-3-one;
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4-(3,4-Dichlorophenyl)-2-[2-(4-methyl-[1,4]diazepan-1-yl)-benzylidene]-
thiomorpholin-
3-one;
4-(3,4-Dichlorophenyl)-2-[2-(2,4,6-trimethylpiperazin-1-yl)-benzylidene]-
thiomorpholin-
3-one;
2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thio
morpholin-
3-one;
the (-)-enantiomer of a compound of formula
c~~
o
and pharmaceutically acceptable salts thereof; wherein R is H or CH3;
a compound of formula
cp
o
and pharmaceutically acceptable salts thereof; wherein R is H or CH3;
(-)-3(S)-[[2-(4-methyl-1-piperazinyl)phenyl]methyl]-1-[4-
(trifluoromethyl)phenyl]-2-
pyrrolidinone;
an enantiomeric mixture of (-)-3(S)-[[2-(4-methyl-1-piperazinyl)phenyl]methyl]-
1-(4-
(trifluoromethyl)phenyl]-2-pyrrolidinone; and (+)-3(R)-[[2-(4-methyl-1-
piperazinyl)phenyl]
methyl]-1-[4-(trifluoromethyl)phenyl]-2-pyrrolidinone, or pharmaceutically
acceptable salts
thereof; wherein the ratio of the 3(S)-enantiomer to the (R)-enantiomer is in
excess of 2:1, 5:1
or 99:1;
a compound of formula III
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R
N
.(+)-di-p-toluyl-D-tartaric acid
N O
~N ~ ~ CF3
111
wherein R is H or CH3;
3,4-Dichloro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
4-Fluoro-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-( 1-methyl-2-[2-(4-methylpiperazin-1-yl )-phenyl]-ethyl)-benzam
ide;
3,4-Dichloro-N-( 1-methyl-2-[2-(4-methylpiperazin-1-yl )-phenyl]-propyl)-
benzamide;
3,4-Dichloro-N-methyl-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-
benzamide;
N-Benzyl-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
N-(4-chlorobenzyl)-N-(2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-(2-{2-[methyl-(1-methylpyrolidin-2-ylmethyl)-amino]-phenyl}-
ethyl)-
benzamide;
3,4-Dichloro-N-{2-[2-( 1-methyl-octahydro-pyrrolo[2,3-c]pyridin-6-yl)-phenyl]-
ethyl}-
benzamide;
3,4-Dichloro-N-{2-[2-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-phenyl]-ethyl}-
benzamide;
3,4-Dichloro-N-{2-[2-(1-methylpiperidin-4-yl)-phenyl]-ethyl)-benzamide;
3,4-Dichloro-N-{2-[2-(2-dimethylaminoethoxy)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2-dimethylamino-ethylsulfanyl)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2-pyrrolidin-1-ylethoxy)-phenyl]-ethyl}-benzamide;
4-Chloro-N-{2-[2-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-benzamide;
4-Chloro-N-(2-{2-[methyl-(2-morpholin-4-yl-ethyl)-amino]-phenyl}-ethyl)-
benzamide;
2-(4-Chloro-phenyl)-N-{2-[2-(4-methylpiperazin-1-yl)-phenyl]-ethyl}-acetamide;
N-{2-[2-(4-Methylpiperazin-1-yl)-phenyl]-ethyl}-N-phenylacetam ide;
N-{2-(2-(4-Methylpiperazin-1-yl)-phenyl]-ethyl}-isonicotinamide;
N-{2-[2-(1-Azabicyclo[2.2.2]oct-4-yl)-phenyl]-ethyl}-N-methylbenzamide;
N-{2-[2-(1,4-Dimethylpiperidin-4-yl)-phenyl]-ethyl}-4-fluorobenzamide;
4-Fluoro-N-{2-[2-(9-methyl-3,9-diazabicyclo[3.3.1 ]non-3-yl)-phenyl]-ethyl}-
benzamide;
N-(2-[2-(1,4-Diazabicyclo[3.3.1]non-4-yl)-phenyl]-ethyl}-N-methylbenzamide;
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N-{1-Methyl-2-[2-(5-methyl-2,5-diazabicyclo[2.2.1 ]hept-2-yl)-phenyl]-ethyl}-
benzamide;
2,4-Dichloro-N-methyl-N-{ 1-methyl-2-[2-(3-methyl-3,8-diazabicyclo[3.2.1 ]oct-
8-yl)-
phenyl]-ethyl}-benzamide;
N-{2-[2-(4-Methyl-octahydroquinoxalin-1-yl)-phenyl]-ethyl}-benzamide;
N-{2-[2-(1-Ethylpyrrolidin-2-ylmethoxy)-phenyl]-ethyl}-benzamide;
5-Phenyloxazole-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-
ethyl}-
amide;
amide;
amide;
amide;
5-Phenylthiophene-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-
ethyl}-
5-Methylthiophene-2-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-
ethyl}-
4-Fluoronaphthalene-1-carboxylic acid {2-[2-(4-methylpiperazin-1-yl)-phenyl]-
ethyl}-
5-Fluoro-1 H-indole-2-carboxylic acid {2-[2-(4-methyl-piperazin-1-yl)-phenyl]-
ethyl}-
amide;
4-Chloro-N-{2-[2-(3,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide;
3,4-Dichloro-N-{2-[2-(2,4,5-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide;
and
3,4-Dichloro-N-{2-[2-(2,4,6-trimethylpiperazin-1-yl)-phenyl]-ethyl}-benzamide.
Methods for making the 5-HT~B receptor antagonists of the formula I or II
described
above are disclosed in the above-listed patents and published patent
applications
incorporated by reference herein, including, for example, U.S. Patent Nos.
6,462,048;
6,258,953; 6,380,186; and 6,323,229; U.S. Patent Publication Nos. 2002/0091119
and
2003/0083337.
The GABA modulators suitable for use in the present invention include, for
example,
compounds of the formula
23 R22
H2NC CH2COOH
R21
wherein R2, is a straight or branched alkyl group having from 1 to 6 carbon
atoms, phenyl, or
cycloalky having from 3 to 6 carbon atoms; RZZ is hydrogen or methyl; and Rz3
is hydrogen,
methyl or carboxyl; and the pharmaceutically acceptable salts thereof.
The GABA modulators suitable for use in the present invention include, as
another
example, compounds of the formula
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H2N C2-C C2-COOR2a
C~
~CH2~n3
wherein R24 is a hydrogen atom or a C~-Cs alkyl radical and n3 is 4,5, or 6;
and the
pharmaceutically acceptable salts thereof.
Examples of GABA modulators include, but are not limited to, muscimol,
progabide,
riluzole, baclofen, gabapentin (Neurontin~), vigabatrin, tiagabine
(Gabitril~), lamotrigine
(Lamictal~), pregabalin, topiramate (Topamax~), a prodrug thereof or a
pharmaceutically
acceptable salt of the GABA modulator or prodrug thereof. It will be
recognized by those
skilled in the art in light of this disclosure that other GABA modulators are
also useful in the
combinations, pharmaceutical compositions, methods and kits of this invention.
The GABA modulators disclosed herein are prepared by methods well known to
those skilled in the art. Specifically, the following patents and patent
applications exemplify
GABA modulators which can be used in the combinations, pharmaceutical
compositions,
methods and kits of this invention, and refer to methods of preparing those
GABA modulators:
U.S. Pat. No. 3,242,190 (specifically, muscimol); U.S. Pat. No. 4,094,992
(specifically,
progabide); U.S. Pat. No. 4,370,338 (specifically, riluzole); U.S. Pat. No.
3,471,548
(specifically, baclofen); U.S. Pat. No. 4,024,175 (specifically, gabapentin);
U.S. Pat. No.
3,960,927 (specifically, vigabatrin); U.S. Pat. No. 5,010,090 (specifically,
tiagabine); U.S. Pat.
No. 4,602,017 (specifically, lamotrigine); U.S. Pat. No. 6,028,214
(specifically, pregabalin);
and U.S. Pat. No. 4,513,006 (specifically, topiramate). U.S. Pat. Nos.
4,024,175 and
6,028,214 are incorporated by reference herein.
Gabapentin, 1-(aminomethyl)cyclohexane acetic acid, is an anticonvulsant
indicated
as adjunctive therapy in the treatment of partial seizures with or without
secondary
generalization in adults with epilepsy. Gabapentin and its methods of use are
described in
U.S. Pat. Nos. 4,024,175 and 4,087,544 incorporated herein by reference in
their entirety.
It will be recognized that certain of the GABA modulators used in the
pharmaceutical
compositions, methods and kits of this invention contain either a free
carboxylic acid or a free
amine group as part of the chemical structure. Thus, this invention includes
pharmaceutically
acceptable salts of those carboxylic acids or amine groups.
Where the compounds of formula I or II or the GABA modulators of use in the
invention have at least one asymmetric center, they may accordingly exist as
enantiomers.
Where the compounds according to the invention possess two or more asymmetric
centers,
they may additionally exist as diastereoisomers. It is to be understood that
all such isomers
and mixtures thereof in any proportion are encompassed within the scope of the
present
invention. Gabapentin may be in the form of the crystalline monohydrate as
described in
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EP340677 which is incorporated herein by reference or the anhydrous
crystalline form as
described in WO 03031391.
The pharmaceutically-acceptable cationic salts of GABA modulators containing
free
carboxylic acids may be readily prepared by reacting the free acid form of the
GABA
modulator with an appropriate base, usually one equivalent, in a co-solvent.
Typical bases are
sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium
methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline,
diethanolamine,
piperazine and tromethamine. The salt is isolated by concentration to dryness
or by addition
of a non-solvent. In many cases, salts are preferably prepared by mixing a
solution of the acid
with a solution of a different salt of the cation (e.g., sodium or potassium
ethylhexanoate,
magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the
desired cationic
salt precipitates, or can be otherwise isolated by concentration and/or
addition of a non-
solvent.
The pharmaceutically acceptable acid addition salts of GABA modulators
containing
free amine groups may be readily prepared by reacting the free base form of
the GABA
modulator with the appropriate acid. When the salt is of a monobasic acid
(e.g., the
hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the
hydrogen form of a
dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen
form of a tribasic
acid (e.g., the dihydrogen phosphate, the citrate), at least one molar
equivalent and usually a
molar excess of the acid is employed. However, when such salts as the sulfate,
the
hemisuccinate, the hydrogen phosphate or the phosphate are desired, the
appropriate and
exact chemical equivalents of acid will generally be used. The free base and
the acid are
usually combined in a co-solvent from which the desired salt precipitates, or
can be otherwise
isolated by concentration and/or addition of a non-solvent.
In the preferred kits of the present invention, the pharmaceutical composition
comprising a ~y-aminobutyric acid modulator is a pharmaceutical composition
comprising one
of the particularly preferred y-aminobutyric acid modulators as defined above,
and the
pharmaceutical composition comprising a 5-HT~B receptor antagonist is a
pharmaceutical
composition comprising one of the particularly preferred 5-HT~B receptor
antagonists as
defined above.
The preferred methods of treatment of the present invention are those methods
that
employ a particularly preferred y-aminobutyric acid modulator and particularly
preferred 5-
HT~B receptor antagonist as defined above.
Also preferred are those methods that employ a particularly preferred y-
aminobutyric
acid modulator and a particularly preferred 5-HT,B receptor antagonist or a
pharmaceutical
compositions) of the present invention, as defined above, for treating
migraine, depression,
obsessive compulsive disorder, post-traumatic stress disorder (PTSD), and
eating disorders.
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Preferably, the combinations of pharmaceutically active compounds of the
present
invention show a synergistic effect and/or show less side effects, as compared
to the
individual compounds, when treating a mammal, preferably a human. Thus, in
treating a
particular disease, at a specific dosage level, the combinations of
pharmaceutically active
compounds of the present invention show a better activity than the activity
which could be
expected when administering the individual compounds, less or less severe side
effects than
could be expected when administering the individual compounds, or a
combination of a better
activity and of less or less severe side effects than could be expected when
administering the
individual compounds.
The expression "pharmaceutically acceptable salts" includes both
pharmaceutically
acceptable acid addition salts and pharmaceutically acceptable cationic salts.
Compounds of the formula I and II and their pharmaceutically acceptable salts,
and y-
aminobutyric acid modulators and their pharmaceutically acceptable salts are
hereinafter also
referred to, collectively, as "the active compounds." Compounds of the formula
I or II are
useful in the treatment of hypertension, depression, generalized anxiety
disorder, phobias
such as agoraphobia, social phobia and simple phobias, posttraumatic stress
syndrome,
avoidant personality disorder, sexual dysfunction such as premature
ejaculation, eating
disorders such as anorexia nervosa and bulimia nervosa, obesity, chemical
dependencies
such as addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine and
benzodiazepines,
cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive
disorder, panic
disorder, memory disorders such as dementia, amnestic disorders, and age-
related cognitive
decline (ARCD), Parkinson's diseases such as dementia in Parkinson's disease,
neuroleptic-
induced parkinsonism and tardive dyskinesias, endocrine disorders such as
hyperprolactinaemia, vasospasm, particularly in the cerebral vasculature,
cerebellar ataxia,
gastrointestinal tract disorders, such as involving changes in motility and
secretion, negative
symptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome,
stress
incontinence, Tourette syndrome, trichotillomania, kleptomania, male
impotence, cancer such
as small cell lung carcinoma, chronic paroxysmal hemicrania and headache, such
as
headache associated with vascular disorders. Similarly, the compositions of
the present
invention are useful in the treatment of the disorders or conditions listed in
this paragraph.
The affinities of the compounds of the formula I for the various serotonin-1
receptors
can be determined using standard radioligand binding assays as described in
the literature.
The 5-HT,A affinity can be measured using the procedure of Hoyer et al. (Brain
Res., 376, 85
(1986)). The 5-HT~B affinity can be measured using the procedure of Heuring
and Peroutka
(J. Neurosci., 7, 894 (1987)). The activity of the compounds of the formula I
or II at the 5-
HT~e binding site, the activity for 5-HT~A binding ability, and the agonist
and antagonist
activities of the compounds of the formula I or II at 5-HT~A and 5-HT~e
receptors may be
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determined as described in U.S. Patent No. 6,380,186. All 5-HT,e receptor
antagonists that
were tested exhibited ICSO's less than 0.60 pM for 5-HT,e affinity and ICSO s
less than 1.0 pM
for 5-HT,A affinity. Similarly, the activity at the 5-HT,e binding site, the
activity for 5-HT~A
binding ability, and the agonist and antagonist activities of the compositions
of the present
invention may be determined using the procedures described for the compounds
in formula I
in U.S. Patent No. 6,380,186.
In the present invention, the 5-HT~B receptor antagonists of formula I or II
and the y-
aminobutyric acid modulators may also be further combined with one or more
other
therapeutic agents, for instance, different antidepressant agents such as
tricyclic
antidepressants such as amitriptyline, dothiepin, doxepin, trimipramine,
butripyline,
clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline
or protriptyline,
monoamine oxidase inhibitors such as isocarboxazid, phenelzine or
tranylcyclopramine or
monoamine reuptake inhibitors such as fluvoxamine, sertraline, fluoxetine or
paroxetine,
and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian
agents such as
levodopa, preferably in combination with a peripheral decarboxylase inhibitor
such as
benserazide or carbidopa. It is to be understood that the present invention
covers the
combination of a 5-HT~B receptor antagonists of formula I or II or a
pharmaceutically
acceptable salt thereof with a ~y-aminobutyric acid modulator or a
pharmaceutically acceptable
salt thereof and with one or more such therapeutic agents.
The combination of the compounds of the formula I or II or the
pharmaceutically
acceptable salts thereof and a y-aminobutyric acid modulator or a
pharmaceutically
acceptable salt thereof is also referred herein to as "the active
combination." The active
combinations are useful psychotherapeutics and may be used in the treatment of
disorders
the treatment of which is facilitated by enhanced serotonergic
neurotransmission such as
hypertension, depression, generalized anxiety disorder, phobias such as
agoraphobia, social
phobia and simple phobias, posttraumatic stress syndrome, avoidant personality
disorder,
sexual dysfunction such as premature ejaculation, eating disorders such as
anorexia nervosa
and bulimia nervosa, obesity, chemical dependencies such as addictions to
alcohol, cocaine,
heroin, phenolbarbitol, nicotine and benzodiazepines, cluster headache,
migraine, pain,
Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory
disorders such
as dementia, amnestic disorders, and age-related cognitive decline (ARCD),
Parkinson's
diseases such as dementia in Parkinson's disease, neuroleptic-induced
parkinsonism and
tardive dyskinesias, endocrine disorders such as hyperprolactinaemia,
vasospasm,
particularly in the cerebral vasculature, cerebellar ataxia, gastrointestinal
tract disorders, such
as involving changes in motility and secretion, negative symptoms of
schizophrenia,
premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence, Tourette
syndrome,
trichotillomania, kleptomania, male impotence, cancer such as small cell lung
carcinoma,
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chronic paroxysmal hemicrania and headache, such as headache associated with
vascular
disorders.
Activity of the active combinations as antidepressants and related
pharmacological
properties can be determined by methods (1 )-(3) below, which are described in
Koe, B. et al.
Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700
(1983).
Specifically, activity can be determined by studying (1 ) their ability to
affect the efforts of mice
to escape from a swim-tank (Porsolt mouse "behavior despair" test), (2) their
ability to
potentiate 5-hydroxytryptophan-induced behavioral symptoms in mice in vivo,
and (3) their
ability to block the uptake of serotonin, norepinephrine and/or dopamine by
synaptosomal rat
brain cells in vitro. The ability of the active combinations to counteract
reserpine hypothermia
in mice in vivo can be determined according to the methods described in U.S.
Pat. No.
4,029,731. The activity of the active combinations as antidepressants and
related
pharmacological properties also can be determined by methods (4)-(8)) below.
Specifically,
activity can be determined by studying (4) their ability to reverse the stress-
induced decrease
in sucrose intake in rodents described in Papp, M. et al., European Journal of
Pharmacolopy,
261, 141-147 (1994), (5) learned helplessness paradigm described in Martin, P
et al., Life
Sciences, 48, 2505-2511 (1991 ), (6) reversing the behavioral deficits of
olfactory
bulbectomized rats described in Broekkamp, CL et al., Pharmacology,
Biochemistry and
Behavior, 13, 643-646 (1980), (7) increasing down-regulation or
desensitization of beta-
adrenergic receptors described in Mishra, R. et al., Neuropharmacolo4y, 19,
983-987 (1980),
and (8) increasing extracellular levels of serotonin, norepinephrine, and/or
dopamine in the
prefrontal cortex of freely-moving rodents by in vivo dialysis described in
Millan, MJ et al.,
European Journal of Neuroscience, 12, 1079-1095 (2000).
Activity of the active combinations of the invention for the treatment of
obsessive
compulsive disorders can be assessed (1 ) by measuring the attenuation of
lever-pressing in
the rat, described by Joel, D. and Avisar, A. in Behavioral Brain Research,
123, 77-87 (2001 );
(2) disruption of spontaneous alternation behavior in rat as exemplified by
Yadin, E. et al in
Pharmacology Biochemistry and Behavior, 40, 311-315 (1991 ): (3) a schedule-
induced
polydipsia assay in rat as disclosed in US Patent 5,356,910 (Kongsamut et al,
Hoechst
Roussel Pharmaceuticals) issued October 18, 1994. Activity of the active
combinations of the
invention for the treatment of sexual dysfunction can be assessed using the
methods
described in Hillegaart, V. and Ahlenius, S. in British Journal of
Pharmacology, 125, 1733-
1743 (1998).
The compositions of the present invention may be formulated in a conventional
manner using one or more pharmaceutically acceptable carriers. Thus, the
active compounds
or the active combinations of the invention may be formulated for oral,
buccal, intranasal,
parenteral (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous
or through an
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implant) nasal, vaginal, sublingual, rectal o topical administration or in a
form suitable for
administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of,
for
example, tablets or capsules prepared by conventional means with
pharmaceutically
acceptable excipients such as binding agents such as pregelatinized maize
starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers such as
lactose, microcrystalline
cellulose or calcium phosphate; lubricants such as magnesium stearate, talc or
silica;
disintegrants such as potato starch or sodium starch glycolate; or wetting
agents such as
sodium lauryl sulphate. The tablets may be coated by methods well known in the
art. Liquid
preparations for oral administration may take the form of, for example,
solutions, syrups or
suspensions, or they may be presented as a dry product for constitution with
water or other
suitable vehicle before use. Such liquid preparations may be prepared by
conventional means
with pharmaceutically acceptable additives such as suspending agents such as
sorbitol syrup,
methyl cellulose or hydrogenated edible fats; emulsifying agents such as
lecithin or acacia,
non-aqueous vehicles such as almond oil, oily esters or ethyl alcohol; and
preservatives such
as methyl or propyl p-hydroxybenzoates or sorbic acid.
For buccal administration, the composition may take the form of tablets or
lozenges
formulated in conventional manner.
The active compounds or the active combinations of the invention may be
formulated
for parenteral administration by injection, including using conventional
catheterization
techniques or infusion. Formulations for injection may be presented in unit
dosage form, for
example, in ampoules or in multi-dose containers, with an added preservative.
The
compositions containing the active combinations may take such forms as
suspensions,
solutions or emulsions in oily or aqueous vehicles, and may contain
formulating agents such
as suspending, stabilizing and/or dispersing agents. Alternatively, the active
ingredient may
be in powder form for reconstitution with a suitable vehicle, for example,
sterile pyrogen-free
water, before use.
The active compounds or the active combinations of the invention may also be
formulated in rectal compositions such as suppositories or retention enemas,
for example,
containing conventional suppository bases such as cocoa butter or other
glycerides.
Compositions for vaginal administration are preferably suppositories that may
contain, in
addition to the active substance, excipients such as cocoa butter or a
suppository wax.
Compositions for nasal or sublingual administration are also prepared with
standard
excipients well known in the art.
For intranasal administration or administration by inhalation, the active
compounds or
the active combinations of the invention are conveniently delivered in the
form of a solution or
suspension from a pump spray container that is squeezed or pumped by the
patient or as an
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aerosol spray presentation from a pressurized container or a nebulizer, with
the use of a
suitable propellant, for example, dichlorodifluoromethane,
trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case
of a pressurized
aerosol, the dosage unit may be determined by providing a valve to deliver a
metered
amount. The pressurized container or nebulizer may contain a solution or
suspension of the
active compounds or the active combinations. Capsules and cartridges, made,
for example,
from gelatin, for use in an inhaler or insufflator may be formulated
containing a powder mix of
an active compound and a suitable powder base such as lactose or starch.
The pharmaceutical compositions of the present invention can consist of a
combination of immediate release and controlled release characteristics. Such
compositions
can take the form of combinations of the active ingredients that range in size
from
nanoparticles to microparticles or in the form of a plurality of pellets with
different release
rates. The tablet or capsule composition of the present invention can contain
a 5-HT~B
receptor antagonist of the formula I or II in sustained or controlled release
form and the y
aminobutyric acid modulator in an immediate release form. Alternatively, the 5-
HT,B receptor
antagonist can be in immediate release form and the y-aminobutyric acid
modulator can be in
sustained or controlled release form.
An exemplary dose of the active combinations of the invention for oral,
parenteral or
buccal administration to the average adult human for the treatment of the
conditions referred
to above, such as depression, is about 0.1 to about 200 mg of the active
compound of
formula I or II and of about 0.1 to about 100 mg of the y-aminobutyric acid
modulator per unit
dose which could be administered, for example, 1 to 4 times per day.
The composition of this invention may contain, for example, gabapentin;
pregabalin;
or a pharmaceutically acceptable salt thereof as the y-aminobutyric acid
modulator and 4
benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, 4-(3,4
dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-
one, or 2-[2-(4-
methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethyl-phenyl)-thiomorpholin-
3-one as the 5-
HT,e antagonist. An exemplary daily dose of the y-aminobutyric acid modulator
in a
pharmaceutical composition of this invention for oral, parenteral, rectal or
buccal
administration to the average adult human for the treatment of the conditions
referred to
above is from about 0.1 to about 300 mg of y-aminobutyric acid modulator per
unit dose
administered 1 to 3 times per day. Exemplary and preferred doses for y-
aminobutyric acid
modulators are determined on a compound by compound basis. 4-benzyl-2-[2-(4-
methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, 4-(3,4-dichlorophenyl)-
2-[2-(4-
methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, or 2-[2-(4-
methylpiperazin-1-yl)-
benzylidene]-4-(4-trifluoromethyl-phenyl)-thiomorpholin-3-one may each be
present in an
amount between about 0.1 and about 200 mg, preferably about 0.3 to about 100
mg.
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Aerosol formulations for treatment of the conditions referred to above, for
example,
migraine, in the average adult human are preferably arranged so that each
metered dose or
"puff' of aerosol contains about 20 pg to about 1000 pg of the compound of
formula I or II.
The overall daily dose with an aerosol will be within the range about 100 ~g
to about 10 mg.
Administration may be several times daily, for example 2, 3, 4 or 8 times,
giving for example,
1, 2 or 3 doses each time. Aerosol formulations containing a compound of
formula I or II and
a y-aminobutyric acid modulator for treatment of the conditions referred to
above in the
average adult human are preferably arranged so that each metered dose or
"puff' of aerosol
contains about 100 wg to about 10,000 pg of the compound of formula I formula
I or II and
about 100 ~g to about 30,000 pg of the r-aminobutyric acid modulator. The
overall daily dose
with an aerosol will be within the range about 100 pg to about 20,000 ~g of
the compound of
formula I or II and about 100 ~g to about 60,000 ~g of the y-aminobutyric acid
modulator.
Administration may be several times daily, for example 1, 3, 4 or 8 times,
giving for example,
1, 2 or 3 doses each time.
The y-aminobutyric acid modulator and the 5-HT~B receptor antagonists of
formula I or
II may be administered either alone or in combination with pharmaceutically
acceptable
carriers by either of the routes previously indicated, and such administration
can be carried
out in both single and multiple dosages. More particularly, this active
combination can be
administered in a wide variety of different dosage forms, i.e., they may be
combined with
various pharmaceutically-acceptable inert carriers in the form of tablets,
capsules, lozenges,
troches, hard candies, powders, sprays, aqueous suspension, injectable
solutions, elixirs,
syrups, and the like. Such carriers include solid diluents or fillers, sterile
aqueous media and
various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical
formulations can
be suitably sweetened and/or flavored by means of various agents of the type
commonly
employed for such purposes. In general, the compounds of formula I or II are
present in such
dosage forms at concentration levels ranging from about 0.1 % to about 95% by
weight of the
total composition, i.e., in amounts which are sufficient to provide the
desired unit dosage, and
a ~y-aminobutyric acid modulator is present in such dosage forms at
concentration levels
ranging from about 0.1 % to about 95% by weight of the total composition,
i.e., in amounts
which are sufficient to provide the desired unit dosage.
The y-aminobutyric acid modulator and the 5-HT~B receptor antagonists of
formula I or
II may be administered together or separately. When administered separately,
the y-
aminobutyric acid modulators and the compounds of formula I or II may be
administered in
either order, provided that after administration of the first of the two
active ingredients, the
second active ingredient is administered within 24 hours or less, preferably
12 hours or less.
A preferred dose ratio of a y-aminobutyric acid modulator to a compound of
formula I
or II in the active combination formulation for oral, parenteral or buccal
administration to the
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average adult human for the treatment of the conditions referred to above is
from about 0.001
to about 1000, preferably from about 0.01 to about 100.
When referring to these preformulation compositions as homogeneous, it is
meant
that the active ingredients is dispersed evenly throughout the composition so
that the
composition may be readily subdivided into equally effective unit dosage forms
such as
tablets, pills and capsules. This solid preformulation composition is then
subdivided into unit
dosage forms of the type described above containing from about 0.1 to about
2000 mg of
each of the active ingredients of the present invention. Typical unit dosage
forms contain from
about 1 to about 300 mg, for example about 1, 2, 5, 10, 25, 50 or 100 mg, of
the active
ingredient. The tablets or pills of the novel composition can be coated or
otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For
example, the tablet or pill can comprise an inner dosage and an outer dosage
component, the
latter being in the form of an envelope over the former. The two components
can be
separated by an enteric layer which serves to resist disintegration in the
stomach and permits
the inner component to pass intact into the duodenum or to be delayed in
release. A variety of
materials can be used for such enteric layers or coatings, such materials
including a number
of polymeric acids and mixtures of polymeric acids with such materials as
shellac, cetyl
alcohol and cellulose acetate.
The dosage of active ingredients in the compositions and methods of this
invention
may be varied; however, it is necessary that the amount of the active
ingredients in such
compositions be such that a suitable dosage form is obtained. The selected
dosage depends
upon the desired therapeutic effect, on the route of administration, the
particular compounds
administered, the duration of the treatment, and other factors. All dosage
ranges and dosage
levels mentioned herein refer to each pharmaceutically active compound present
in the
pharmaceutical compositions and kits of the present invention, as well as
those used in the
methods of the present invention. Generally, dosage levels of between about
0.01 and about
100 mg/kg of body weight daily are administered to humans and other animals,
e.g.,
mammals. A preferred dosage range in humans is about 0.1 to about 50 mg/kg of
body
weight daily which can be administered as a single dose or divided into
multiple doses. A
preferred dosage range in mammals other than humans is about 0.01 to about
10.0 mg/kg of
body weight daily which can be administered as a single dose or divided into
multiple doses.
A more preferred dosage range in mammals other than humans is about 0.1 to
about 5.0
mg/kg of body weight daily which can be administered as a single dose or
divided into
multiple doses.
In general, the pharmaceutical compositions, methods and kits of this
invention, will
be administered at dosages of a therapeutically effective amount of the first
and of the second
active compound in single or divided doses. The term "therapeutically
effective amount" as
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used herein refers to a sufficient amount of the compound to treat the
disorders and disorders
or conditions disclosed herein at a reasonable benefit/risk ratio applicable
to any medical
treatment.
The specific therapeutically effective dose level for any particular patient
will depend
upon a variety of factors including the disorder being treated and the
severity of the disorder;
activity of the specific compound employed; the specific composition employed;
the age.
However, some variation in dosage will necessarily occur depending upon the
condition of the
subject being treated. The person responsible for administration will, in any
event, determine
the appropriate dose for the individual subject.
The dosage amounts set forth in this description and in the appendant claims
may be
used, for example, for an average human subject having a weight of about 65 kg
to about 70
kg. The skilled practitioner will readily be able to determine any variation
in the dosage
amount that may be required for a subject whose weight falls outside the about
65 kg to about
70 kg range, based upon the medical history of the subject. The pharmaceutical
combinations may be administered on a regimen of up to 6 times per day,
preferably 1 to 3
times per day, such as 2 times per day or once daily.
The present invention also encompasses treatment with a combination of active
ingredients which may be administered separately. Accordingly, the invention
also relates to
combining separate pharmaceutical compositions in kit form. Thus, in one
embodiment, the
kit comprises two separate pharmaceutical compositions: a r-aminobutyric acid
modulator or
a pharmaceutically acceptable salt of said y-aminobutyric acid modulator; and
a 5-HT,B
receptor antagonist of the formula I or II or a pharmaceutically acceptable
salt of said 5-HT,B
receptor antagonist. The kit also comprises a container for containing the
separate
compositions such as a divided bottle or a divided foil packet, however, the
separate
compositions may also be contained within a single, undivided container.
Typically, the kit
comprises directions for the administration of the separate components. The
kit form is
particularly advantageous when the separate components are preferably
administered in
different dosage forms (e.g., oral and parenteral), are administered at
different dosage
intervals, or when titration of the individual components of the combination
is desired by the
prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well
known in
the packaging industry and are being widely used for the packaging of
pharmaceutical unit
dosage forms, such as tablets, capsules, and the like. It may be desirable to
provide a
memory aid on the kit, e.g., in the form of numbers next to the tablets or
capsules whereby
the numbers correspond with the days of the regimen which the dosage form so
specified
should be ingested. Another example of such a memory aid is a calendar printed
on the card
e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week,
Monday, Tuesday,
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. . . " etc. Other variations of memory aids will be readily apparent. A
"daily dose" can be a
single tablet or capsule or several tablets or capsules to be taken on a given
day. Also, a daily
dose of a ~y-aminobutyric acid modulator, or a pharmaceutically acceptable
salt of said y-
aminobutyric acid modulator can consist of one tablet or capsule, while a
daily dose of the 5-
HT,B receptor antagonist of formula I or II or pharmaceutically acceptable
salt of said 5-HT,B
receptor antagonist can consist of several tablets or capsules and vice versa.
The memory
aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to
dispense
the daily doses one at a time in the order of their intended use is provided.
Preferably, the
dispenser is equipped with a memory-aid, so as to further facilitate
compliance with the
regimen. An example of such a memory-aid is a mechanical counter that
indicates the
number of daily doses that has been dispensed. Another example of such a
memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal readout, or
audible reminder
signal which, for example, reads out the date that the last daily dose has
been taken and/or
reminds one when the next dose is to be taken.
In another embodiment, the present invention comprises kits comprising a
pharmaceutical composition, a package, and a package insert. The
pharmaceutical
composition of these kits contains either a r-aminobutyric acid modulator or a
5-HT~B receptor
antagonist of formula I or II. The kits of the present invention containing a
pharmaceutical
composition containing a y-aminobutyric acid modulator differ from known kits
containing a
pharmaceutical composition containing a y-aminobutyric acid modulator in that
on the
package and/or on the package insert of the kits it is stated that the
pharmaceutical
composition is to be administered together with a pharmaceutical composition
containing a 5-
HT,B receptor antagonist. The kits of the present invention containing a
pharmaceutical
composition containing a 5-HT~B receptor antagonist of formula I or II differ
from known kits
containing a pharmaceutical composition containing a 5-HT~B receptor
antagonist in that on
the package and/or on the package insert of the kits it is stated that the
pharmaceutical
composition is to be administered together with a pharmaceutical composition
containing a r-
aminobutyric acid modulator.
The term "together with" as used in the immediately preceding paragraph is
intended
to encompass the simultaneous administration of the two pharmaceutical
compositions (e.g.,
a tablet containing one pharmaceutical composition is to be administered
orally while the
other pharmaceutical composition is administered by way of infusion, two
tablets or capsules
are to be swallowed together, etc.). The term "together with" is also intended
to include the
administration of the two pharmaceutical compositions in a specifically timed
manner, i.e., one
pharmaceutical composition is to be administered a certain time period after
administration of
the other pharmaceutical composition. The time period in which the two
pharmaceutical
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compositions are to be administered must be sufficiently short for the y-
aminobutyric acid
modulator and the 5-HT~B receptor antagonist of formula I or II to exhibit
their activity
contemporaneously, preferably in a synergistic manner. The exact time period
depends on
the specific compounds of the pharmaceutical compositions, the application
route, the kind
and severeness of the disease to be treated, the kind, age, and condition of
the patient to be
treated, etc., and can be determined by a physician using known methods in
combination with
the disclosure of the present invention. Generally, the two compositions are
to be
administered within 24 hours or less, such as 12 hours or less, preferably
within 5 hours,
more preferably within 2 hours, and even more preferably within one hour. Most
preferably,
the two compositions are to be administered at the same time or one
immediately after the
other.
The combinations of this invention, i.e., a y-aminobutyric acid modulator and
a 5-HT~B
receptor antagonist, may be tested for conditions such as, for example,
migraine, depression,
obsessive compulsive disorder, post-traumatic stress disorder (PTSD), and
eating disorders
according to the procedures.
The invention is further illustrated by, but by no means limited to, the
following
examples.
EXAMPLE 1
A pharmaceutical composition is prepared by combining 4-benzyl-2-[2-(4
methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, 4-(3,4-dichlorophenyl)-
2-[2-(4
methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one, or 2-[2-(4-
methylpiperazin-1-yl)
benzylidene]-4-(4-trifluoromethyl-phenyl)-thiomorpholin-3-one as the 5-HT,B
receptor
antagonist with a y-aminobutyric acid modulator that is either gabapentin or
pregabalin in a
pharmaceutically acceptable carrier. The composition contains about 1.0 mg to
about 160 mg
of the 5-HT,B receptor antagonist and about 5 mg to about 200 mg of the y-
aminobutyric acid
modulator to deliver on a daily basis The composition is administered to a
patient for the
treatment of depression on a daily, twice daily, or three times daily basis.
It should be understood that the present invention is not limited to the
embodiments
described herein. Numerous modifications can be made by one skilled in the art
having the
benefits of the teachings given here. Such modifications should be taken as
being
encompassed within the scope of the present invention as set forth in the
appended claims.
